Antifungal stewardship: Core elements to success
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Antimicrobial stewardship has been defined as coordinated interventions designed to improve and measure appropriate use of antimicrobial agents by promoting the selection of optimal drug regimens.
The CDC first developed the Core Elements of Antibiotic Stewardship in 2014. These guidelines likely apply to antifungal stewardship as well. However, fungal infections can be more complex and may require different considerations for optimal management. Antifungals are not used nearly as much as antibiotics, yet their use is not insignificant. Approximately 3% of hospitalized patients receive a systemic antifungal drug. However, this increases to 7.7% for patients in an ICU. Although antifungals are needed for prophylaxis or treatment of complex infections, data suggest these agents are often overprescribed or used inappropriately. Many of the available antifungal agents are expensive, so overuse can put a financial burden on both patients and the health care system. Although the drivers of antifungal overuse are multifactorial, limitations of fungal infection diagnostics as well as potential knowledge gaps are likely contributors.
Recently, an interdisciplinary expert panel of members from the Mycoses Study Group Education and Research Consortium met and developed core elements that relate specifically to antifungal stewardship (see Table).
Importance of antifungal stewardship
A major driver for antifungal stewardship is that invasive fungal infections are associated with significant morbidity and mortality. Invasive fungal infection mortality often exceeds 50% despite antifungal therapy, especially when occurring in immunosuppressed patients. Because most antifungals have complex pharmacokinetic profiles with many drug-drug or drug-food interactions, dosing regimens or drugs may need to be altered to optimize therapy to help improve patient outcomes. Adverse drug reactions are frequently reported with use of these agents, with drug-drug interactions being an important factor leading to these untoward effects.
One of the major factors driving the need for antifungal stewardship is the development of drug resistance. As with antibiotic resistance, antifungal resistance emerged shortly after introduction into clinical practice, but it has been slower to emerge. According to the CDC, approximately 7% of Candida species isolated from blood cultures are resistant to fluconazole. Although Candida albicans is the most common species, resistance is more often associated with Candida glabrata, Candida auris and Candida parapsilosis. C. auris is the most problematic emerging multidrug-resistant yeast because it can cause serious disease and is easily spread between patients within health care facilities. There are reports of some strains of C. auris demonstrating resistance to all classes of antifungal agents, making treatment difficult. In addition, azole-resistant Aspergillus fumigatus has been reported and is on the CDC’s watch list in the 2019 report on antibiotic resistance threats in the United States. Gene modifications are the main mechanism of resistance in A. fumigatus, but other mechanisms such as efflux pumps, transcription factor alterations and compensatory cholesterol import have also been identified. These mutations result in resistance to all currently available azoles.
Interventions
A reasonable starting point for any antifungal stewardship program is to develop disease state guidelines, along with prescriber education. To be successful, these interventions should be combined with other strategies because they are unlikely to be successful alone. Prospective audit and feedback or postprescription review can help encourage guideline adherence by offering advice on patient-specific circumstances, such as drug interactions, or therapy changes based on culture results. This is ideally done by personnel who are knowledgeable or have experience in the diagnosis and treatment of fungal infections, such as infectious diseases physicians and clinical pharmacists. A recent study evaluated the effectiveness of early de-escalation from echinocandin to fluconazole treatment in candidemia. De-escalation within the first 5 days did not have an impact on patient mortality. Early transition to fluconazole for susceptible strains of Candida species appears to be safe and a viable stewardship strategy for patients with hemodynamic stability and adequate source control.
Implementation of prescribing restrictions or preauthorization requirements is another effective way to limit unnecessary antifungal use, but this approach could have an unintended consequence on patient outcomes if optimal treatment is delayed. Therefore, monitoring patient outcomes is recommended if antifungal restrictions are in place.
Other common interventions that programs can implement include an oral conversion policy, antifungal therapeutic drug monitoring and driving optimal use of fungal diagnostics.
Quality metrics
All facilities with antifungal stewardship initiatives should have a mechanism to track antifungal drug use to facilitate change. The two most common metrics for antimicrobial consumption are days of therapy (DOT) and defined daily dose with adjustment according to patient-days, patient admission or days present to account for variations in patient volumes over time. In the U.S., the National Health and Safety Network has developed risk-adjusted metrics for antimicrobial use known as the Standardized Antibiotic Administration Ratio (SAAR). Facilities reporting their antimicrobial use data to this program can access the SAAR for antifungals used predominantly for candidiasis. The SAAR is a ratio of the observed DOT compared with a risk-adjusted expected DOT. A SAAR with a value of greater than 1 would indicate that use was more than what is predicted for the facility or patient care area. Although useful for measuring quantity of antimicrobial use, these measures do not account for prescribing quality or appropriateness, so programs should also assess patient-level outcomes, when possible. Although determining the impact of mortality and hospital length of stay are challenging because of the numerous factors that can affect these things, other metrics might be more obtainable. Examples of quality-of-care measures that programs could monitor include number of cases reviewed, number of guidelines developed, number of IV-to-oral conversions and number of recommendations made with acceptance rate.
Antifungal stewardship is a more specialized area of stewardship that requires a different level of experience and expertise because of the complexity of management of invasive fungal infections. Implementation of the core recommendations for antifungal stewardship gives facilities the blueprint to implement effective interventions to improve use of these important drugs with the goal to improve patient outcomes and reduce untoward effects. Although antifungal resistance has been slow to evolve, implementation of stewardship initiatives to improve the use of these agents will help improve the care of patients and hopefully keep resistance low.
- References:
- Barlam TF, et al. Clin Infect Dis. 2016;doi:10.1093/cid/ciw118.
- Bienvenu AL, et al. J Antimicrob Chemother. 2018;doi:10.1093/jac/dkx388.
- CDC. Antibiotic resistance threats in the United States, 2019. Atlanta, GA: U.S. Department of Health and Human Services, CDC; 2019. https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf. Accessed June 22, 2021.
- Johnson MD, et al. J Infect Dis. 2020;doi:10.1093/infdis/jiaa394.
- Moreno-Garcia E, et al. Open Forum Infect Dis. 2021;doi:10.1093/ofid/ofab250.
- Pappas PG, et al. Clin Infect Dis. 2016;doi:10.1093/cid/civ933.
- Urbancic KF, et al. Current Opin Infect Dis. 2018: DOI:10.1097/QCO.0000000000000497.
- For more information:
- Jeff Brock, PharmD, MBA, BCPS-AQ ID, is an infectious disease pharmacy specialist at Mercy Medical Center in Des Moines, Iowa. He can be reached at: jbrock@mercydesmoines.org.
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